HER-2 binding antibodies

Abstract

Monoclonal antibodies that specifically bind to HER2, or a fragment or derivative thereof or a polypeptide that contains at least a portion of said antibody that is sufficient to confer specific HER2 binding to the polypeptide. Said antibodies bind to the human Fc receptor and induce FcR mediated signaling pathways. The antibodies according to the invention bind to a different epitope than trastuzumab. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody.

The invention claimed is: 
     
       1. A fragment or derivative of a monoclonal antibody selected from the group consisting of:
 i. B100 comprising light chain variable region CDR amino acid sequences CDR-L1 of SEQ ID NO: 34, CDR-L2 of SEQ ID NO: 40, and CDR-L3 of SEQ ID NO: 46, and heavy chain variable region CDR amino acid sequences CDR-H1 of SEQ ID NO: 16, CDR-H2 of SEQ ID NO: 22, and CDR-H3 of SEQ ID NO: 28; 
 ii. C074 comprising light chain variable region CDR amino acid sequences CDR-L1 of SEQ ID NO: 31, CDR-L2 of SEQ ID NO: 37, and CDR-L3 of SEQ ID NO: 43, and heavy chain variable region CDR amino acid sequences CDR-H1 of SEQ ID NO: 13, CDR-H2 of SEQ ID NO: 19, and CDR-H3 of SEQ ID NO: 25; 
 iii. C031 comprising light chain variable region CDR amino acid sequences CDR-L1 of SEQ ID NO: 32, CDR-L2 of SEQ ID NO: 38, and CDR-L3 of SEQ ID NO: 44, and heavy chain variable region CDR amino acid sequences CDR-H1 of SEQ ID NO: 14, CDR-H2 of SEQ ID NO: 20, and CDR-H3 of SEQ ID NO: 26; 
 iv. B106 comprising light chain variable region CDR amino acid sequences CDR-L1 of SEQ ID NO: 33, CDR-L2 of SEQ ID NO: 39, and CDR-L3 of SEQ ID NO: 45, and heavy chain variable region CDR amino acid sequences CDR-H1 of SEQ ID NO: 15, CDR-H2 of SEQ ID NO: 21, and CDR-H3 of SEQ ID NO: 27; 
 v. AK57 comprising light chain variable region CDR amino acid sequences CDR-L1 of SEQ ID NO: 35, CDR-L2 of SEQ ID NO: 41, and CDR-L3 of SEQ ID NO: 47, and heavy chain variable region CDR amino acid sequences CDR-H1 of SEQ ID NO: 17, CDR-H2 of SEQ ID NO: 23, and CDR-H3 of SEQ ID NO: 29; and 
 vi. B115 comprising light chain variable region CDR amino acid sequences CDR-L1 of SEQ ID NO: 36, CDR-L2 of SEQ ID NO: 42, and CDR-L3 of SEQ ID NO: 48, and heavy chain variable region CDR amino acid sequences CDR-H1 of SEQ ID NO: 18, CDR-H2 of SEQ ID NO: 24, and CDR-H3 of SEQ ID NO: 30, 
 
       wherein the fragment or derivative specifically binds to HER2, and is at least 2-fold more effective in inducing apoptosis in cells of a cancer cell line than trastuzumab or pertuzumab. 
     
     
       2. The antibody fragment or derivative according to  claim 1 , wherein the fragment or derivative is at least 3-fold more effective in inducing apoptosis in the cells than trastuzumab or pertuzumab. 
     
     
       3. The antibody fragment or derivative according to  claim 2 , wherein the fragment or derivative is at least 4-fold more effective in inducing apoptosis in the cells than trastuzumab or pertuzumab. 
     
     
       4. The antibody fragment or derivative according to  claim 1 , wherein the fragment or derivative induces apoptosis in at least 60% of the cells. 
     
     
       5. The antibody fragment or derivative according to  claim 4 , wherein the fragment or derivative induces apoptosis in at least 75% of the cells. 
     
     
       6. The antibody fragment or derivative according to  claim 1 , wherein the EC50 of the fragment or derivative is less than the EC50 of trastuzumab. 
     
     
       7. The antibody fragment or derivative according to  claim 6 , wherein the EC50 of the fragment or derivative is less 80 ng/ml. 
     
     
       8. The antibody fragment or derivative according to  claim 1 , wherein said fragment or derivative also binds to the human Fc receptor and induces FcR mediated signaling pathways. 
     
     
       9. The antibody fragment or derivative according to  claim 8 , wherein said fragment or derivative increases the Fc receptor signaling activity in an FcγRIIIa assay by at least 10-fold. 
     
     
       10. The antibody fragment or derivative according to  claim 8 , wherein said fragment or derivative binds to a different epitope than trastuzumab. 
     
     
       11. The antibody fragment or derivative according to  claim 8 , wherein said fragment or derivative does not compete with trastuzumab in an epitope competition assay. 
     
     
       12. The antibody fragment or derivative according to  claim 8 , wherein said fragment or derivative does not compete with pertuzumab in an epitope competition assay, except for the antibodies designated as B106 and B115. 
     
     
       13. The antibody fragment or derivative according to  claim 1 , wherein said antibody fragment or derivative is capable of reducing the tumor burden, tumor dissemination and metastasis. 
     
     
       14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody fragment or derivative according to  claim 1 . 
     
     
       15. The antibody fragment or derivative according to  claim 1 , wherein the fragment or derivative comprises a heavy chain variable (VH) region that is at least 90% identical to the VH region of SEQ ID NO: 4 and a light chain variable (VL) region that is at least 90% identical to the VL region of SEQ ID NO: 10. 
     
     
       16. The antibody fragment or derivative according to  claim 1 , wherein the fragment or derivative is a fragment or derivative of a humanized antibody. 
     
     
       17. The antibody fragment or derivative according to  claim 1 , wherein said fragment or derivative comprises a VL region selected from the group of VL regions comprising a CDR-L1 region of SEQ ID NO: 31+n, a CDR-L2 region of SEQ ID NO: 37+n and a CDR-L3 region of SEQ ID NO: 43+n, wherein n is a number selected from the group consisting of 0 to 5. 
     
     
       18. The antibody fragment or derivative according to  claim 1 , wherein the fragment or derivative comprises:
 a) a heavy chain variable (VH) region is at least 90% identical to a VH region selected from the group consisting of VH regions of SEQ ID NO: 1 to 6 and SEQ ID NO: 100 to 101, and 
 b) a light chain variable (VL) region at least 90% identical to a VL region selected from the group consisting of VL regions of SEQ ID NO: 7 to 12 and SEQ ID NO 102 to 104.